cyclic-GDP-ribose

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: cyclic-GDP-ribose
• 英文别名: (2R,3R,4S,5R,13R,14S,15R,16R)-20-amino-3,4,10,14,15-pentahydroxy-8-oxido-8,10-dioxo-7,9,11,25,26-pentaoxa-1,19,21-triaza-17-azonia-8lambda5,10lambda5-diphosphapentacyclo[15.6.1.12,5.113,16.018,23]hexacosa-17(24),18(23),19-trien-22-one；(2R,3R,4S,5R,13R,14S,15R,16R)-20-amino-3,4,10,14,15-pentahydroxy-8-oxido-8,10-dioxo-7,9,11,25,26-pentaoxa-1,19,21-triaza-17-azonia-8λ5,10λ5-diphosphapentacyclo[15.6.1.12,5.113,16.018,23]hexacosa-17(24),18(23),19-trien-22-one
• 化学式: C₁₅H₂₁N₅O₁₄P₂
• 分子量: 557.304
• InChiKey: LGXVTHFFJWVVKZ-AIKIOGRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -6.6
• 重原子数：
  36
• 可旋转键数：
  0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  281
• 氢给体数：
  7
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  nicotinamide guanine dinucleotide 在 bovine CD₃₈/NAD⁺ glycohydrolase 作用下， 以 aq. phosphate buffer 为溶剂， 生成 cyclic-GDP-ribose
  参考文献：
  名称：

  Probing the catalytic mechanism of bovine CD38/NAD+glycohydrolase by site directed mutagenesis of key active site residues

  摘要：

  Bovine CD38/NAD(+) glycohydrolase catalyzes the hydrolysis of NAD(+) to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism. Our recent crystallographic study of its Michaelis complex and covalently-trapped intermediates provided insights into the modalities of substrate binding and the molecular mechanism of bCD38. The aim of the present work was to determine the precise role of key conserved active site residues (Trp118, Glu138, Asp147, Trp181 and Glu218) by focusing mainly on the cleavage of the nicotinamide-ribosyl bond. We analyzed the kinetic parameters of mutants of these residues which reside within the bCD38 subdomain in the vicinity of the scissile bond of bound NAD(+). To address the reaction mechanism we also performed chemical rescue experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. The crucial role of Glu218, which orients the substrate for cleavage by interacting with the N-ribosyl 2'-OH group of NAD(+), was highlighted. This contribution to catalysis accounts for almost half of the reaction energy barrier. Other contributions can be ascribed notably to Glu138 and Asp147 via ground-state destabilization and desolvation in the vicinity of the scissile bond. Key interactions with Trp118 and Trp181 were also proven to stabilize the ribooxocarbenium ion-like transition state. Altogether we propose that, as an alternative to a covalent acylal reaction intermediate with Glu218, catalysis by bCD38 proceeds through the formation of a discrete and transient ribooxocarbenium intermediate which is stabilized within the active site mostly by electrostatic interactions. (C) 2014 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.bbapap.2014.03.014

文献信息

• Yamada, Shinji; Gu, Qu-Ming; Sih, Charles J., Journal of the American Chemical Society, 1994, vol. 116, # 23, p. 10787 - 10788
  作者：Yamada, Shinji、Gu, Qu-Ming、Sih, Charles J.

  DOI：——

  日期：——
• Novel enzymatic cyclizations of pyridine nucleotide analogs: Cyclic-GDP-ribose and cyclic-HDP-ribose
  作者：Fang-Jie Zhang、Charles J. Sih

  DOI：10.1016/0040-4039(95)02004-9

  日期：1995.12

  The cyclase of Aplysia californica catalyzed an alternative mode of cyclization of nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD) to form cyclic-GDP-ribose (cGDPR) and cyclic-HDP-ribose (cHDPR) respectively. In these cyclic nucleotides, the newly formed glycosyl bonds are attached onto the N-7 nitrogen of the purine rings instead of the N-1 nitrogen as in cyclic ADP-ribose (cADPR).
• Probing the catalytic mechanism of bovine CD38/NAD+glycohydrolase by site directed mutagenesis of key active site residues
  作者：Isabelle Kuhn、Esther Kellenberger、Céline Cakir-Kiefer、Hélène Muller-Steffner、Francis Schuber

  DOI：10.1016/j.bbapap.2014.03.014

  日期：2014.7

  Bovine CD38/NAD(+) glycohydrolase catalyzes the hydrolysis of NAD(+) to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism. Our recent crystallographic study of its Michaelis complex and covalently-trapped intermediates provided insights into the modalities of substrate binding and the molecular mechanism of bCD38. The aim of the present work was to determine the precise role of key conserved active site residues (Trp118, Glu138, Asp147, Trp181 and Glu218) by focusing mainly on the cleavage of the nicotinamide-ribosyl bond. We analyzed the kinetic parameters of mutants of these residues which reside within the bCD38 subdomain in the vicinity of the scissile bond of bound NAD(+). To address the reaction mechanism we also performed chemical rescue experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. The crucial role of Glu218, which orients the substrate for cleavage by interacting with the N-ribosyl 2'-OH group of NAD(+), was highlighted. This contribution to catalysis accounts for almost half of the reaction energy barrier. Other contributions can be ascribed notably to Glu138 and Asp147 via ground-state destabilization and desolvation in the vicinity of the scissile bond. Key interactions with Trp118 and Trp181 were also proven to stabilize the ribooxocarbenium ion-like transition state. Altogether we propose that, as an alternative to a covalent acylal reaction intermediate with Glu218, catalysis by bCD38 proceeds through the formation of a discrete and transient ribooxocarbenium intermediate which is stabilized within the active site mostly by electrostatic interactions. (C) 2014 Elsevier B.V. All rights reserved.